Classical cannabinoids such as the marijuana derived cannabinoid Δ9-tetrahydrocannabinol, (Δ9-THC) produce their pharmacological effects through interaction with specific cannabinoid receptors in the body. So far, two cannabinoid receptors have been characterized: CB1 found in the mammalian brain and peripheral tissues and CB2 found only in the peripheral tissues. Compounds which stimulate those receptors have been shown to induce analgesia and sedation, to cause mood elevation including euphoria and dream states, to control nausea and appetite and to lower intraocular pressure. Cannabinoids have also been shown to suppress the immune system and affect the reproductive system. Thus, compounds which stimulate the CB1 and CB2 receptors, directly or indirectly, are potentially useful as oral and topical contraceptive preparations, in treating glaucoma, preventing tissue rejection in organ transplant patients, controlling nausea in patients undergoing chemotherapy, controlling pain and enhancing the appetite in individuals with AIDS Wasting Syndrome.
In addition to acting at the cannabinoid receptors, cannabinoids such as Δ9-THC also affect cellular membranes, thereby producing undesirable side effects such as drowsiness, impairment of monoamine oxidase function and impairment of non-receptor mediated brain function. The addictive and psychotropic properties of cannabinoids also limit their therapeutic value.
Arachidonylethanolamide (anandamide) is an endogenous lipid that binds to and activates the CB1 cannabinoid receptor with approximately equal affinity to that of Δ9-THC. Anandamide also exhibits biochemical and pharmacological properties similar to that of Δ9-THC, albeit with a longer onset time and shorter duration of action. The exact physiological role of anandamide, a cannabinoid agonist, is still not clearly understood. It is known that an enzyme called “anandamide amidase” hydrolyzes anandamide. It is presumed that the magnitude of action and relatively short duration of action of anandamide is due to a rapid inactivation process consisting of carrier-mediated transport into cells followed by intra-cellular hydrolysis by anandamide amidase.
There is considerable interest in developing analogs of anandamide possessing high CB1 receptor affinity and/or metabolic stability. Such analogs may offer a rational therapeutic approach to a variety of disease states, including pain, psychomotor disorders, and multiple sclerosis, in which elevation of anandamide analog levels may bring about a more favorable response with fewer side effects and greater metabolic stability than direct activation of CB1 receptors by anandamide.